Respiratory morbidity is common in infants who have been treated with mechanical ventilation and oxygen therapy for respiratory failure, especially in those who develop BPD (De Paepe et al. 2006; Bancalari and Claure 2008; Caudri et al. 2007). The infant moves from RDS to BPD as the effects of inflammation, mechanical ventilation-induced volutrauma and oxygen (chemotrauma) lead to chronic lung injury and repair. This pattern of injury and repair will eventually overshadow the effects of prematurity and growth restriction alone (Ambalavanan and Carlo 2006; Cook et al. 1996; Dani et al. 2006; Hutchison and Bignall 2008; Jobe and Ikegami 1998). It is still unclear what relative contribution mechanical ventilation and the underlying disease make to the pattern of lung injury seen in BPD especially since the need for mechanical ventilation is a marker for underlying disease severity (Claure and Bancalari 2008).

When considering short-term outcomes such as hospitalisation, infection, wheezing and the results of lung function tests, it is important to remember that BPD is a broad term whose definition and epidemiology has changed significantly over the past four decades (Eber and Zach 2001). For instance, the use of exogenous surfactant and antenatal corticosteroids alongside improvements in mechanical ventilation and oxygen therapy in the early 1990s has dramatically improved survival rates and reduced lung injury amongst those neonates who are born preterm, at very low birth weights or extremely low birth weights (Allen et al. 2003; Doyle 2008; Gerstmann et al. 1996). Moreover, the complexity of the change in BPD definition over time is added to by the observation that lung function testing not only examines the effects of mechanical ventilation on the lung but also looks at what influence the posthospital environment, which may include repeated respiratory infection and cigarette smoke, will have on lung development (Allen et al. 2003; Eber and Zach 2001).

During the first few years following discharge from hospital, children with BPD may have a prolonged requirement for supplemental oxygen and are more likely to be treated for pneumonia and be readmitted to hospital for respiratory infections, such as respiratory syncytial virus (RSV)-induced bronchiolitis (Allen et al. 2003; de Kleine et al. 1990; Baraldi and Filippone 2007; de Mello et al. 2006; Gross et al. 1998; Hjalmarson and Sandberg 2002; Kitchen et al. 1992; Marlow et al. 2006; Thomas et al. 2004). These young infants are reported to have higher incidences of wheezing, ‘asthma-like’ symptoms, hyperreactivity of their airways and increased levels of inflammatory markers (Baraldi and Filippone 2007; Thomas et al. 2004; Attar and Donn 2002; Hennessy et al. 2008). By the time these infants have reached school age, their risk of hospital admission is comparable to those children without a history of mechanical ventilation or BPD. There are conflicting reports as to whether there is an increased (McLeod et al. 1996; Ng et al. 2000; Siltanen et al. 2004) or the same incidence (Kitchen et al. 1992; Northway et al. 1990) of asthma in ELBW/preterm survivors. Other studies suggest that reduced airway function in the first year of life may lead to transient wheeze but no long-term risk of atopy (Martinez et al. 1995).

Lung function measurements in infants are currently restricted to specialist laboratories. Those researchers who have performed measurement of pulmonary function in infants with BPD have shown reductions in lung volumes, impaired ventilation distribution, reduced dynamic compliance, increased airways resistance, evidence of air trapping and reduced expiratory flows compared with contemporaneous individuals and control subjects (Anand et al. 2003; Doyle et al. 1999, 2006; Hakulinen et al. 1996; Jacob et al. 1998; Kulasekaran et al. 2007). These values, although abnormal on many occasions, do not always fall within clinically significant ranges. This may reflect the differing aetiologies and definitions employed to describe BPD (Chan et al. 1989). There is currently much debate and investigation as to whether these abnormalities track into adolescence and adulthood (Doyle et al. 1999, 2006; Blayney et al. 1991; Filippone et al. 2003; Koumbourlis et al. 1996).

BPD is a major cause of long-term respiratory morbidity in adolescents and adults who were ventilated as neonates with respiratory failure. There are many cross-sectional studies investigating respiratory outcome in these individuals who have shown increased prevalence of airflow obstruction, air trapping (hyperinflation and/or loss of lung elasticity) and impairments in the gas exchange properties of the lung, as shown in Table 63.1 (Doyle et al. 1999, 2006; Jacob et al. 1998; Kulasekaran et al. 2007; Pelkonen et al. 1998). Other researchers show no significant differences between those who received assisted ventilation and those who did not (Table 63.1) (Anand et al. 2003; Hakulinen et al. 1996).

Few studies report findings from the same individuals who were mechanically ventilated as a neonate and developed BPD through to late adolescence or adulthood. Those studies that do report three significant findings: Firstly, airflow obstruction is a consistent feature of respiratory function in survivors of BPD. For instance, mean forced expiratory volume in one second (FEV₁) has been reported to be reduced at 2 years of age whilst forced mid-flow values (FEF_{25–75 %}) were less than predicted at 2, 7, 8 and 10 years of age (Blayney et al. 1991; Filippone et al. 2003). Moreover, reduced maximal flows at functional residual capacity in children at 2 years of age were predictive of reduced FEF_{25–75 %} at 8 years of age (Filippone et al. 2003). Secondly, airflow obstruction appeared to improve in some cases over time. Blayney reported that 59 % of the patients with an FEV₁ below 80 % predicted at 7 years of age had increased FEV₁% predicted at 10 years (Blayney et al. 1991), although this improvement may have just reflected regression towards the mean, rather than true improvement. In another study Doyle and colleagues reported an increase in FEV₁ and FEF_{25–75 %} between the ages of 8 and 14 years in a cohort of infants of birth weight <1,501 g (Doyle et al. 1999). Moreover, a number of groups have reported an improvement in the ratio of residual volume (Hakulinen et al. 1996) to total lung capacity (TLC) suggesting that air trapping and/or lung elasticity improves in the teenage years (Doyle et al. 1999; Koumbourlis et al. 1996). There is a suggestion that airway hyperreactivity may contribute to chronic airflow obstruction in those individuals who received mechanical ventilation and developed BPD (Koumbourlis et al. 1996). Of those who had assisted ventilation, a high percentage had reduced FEV₁ (mean 87.9 % SD 18.3 % predicted) and FEF_{25–75 %} (mean 62.3 %, SD 29.0 % predicted) that responded to bronchodilator therapy, and a further half of these cases responded to a histamine airway challenge (Koumbourlis et al. 1996). Thirdly, despite the improvement in lung function over the teenage years, some respiratory impairment persists in adults who had previously had BPD as an infant. For instance, 19-year-olds who had previously had BPD were found to have a mean difference in FEV₁ of −11.3 % predicted (−16.9 to −5.7 %, p < 0.001) compared with controls who had not received assisted ventilation and did not develop BPD (Doyle et al. 2006). Moreover, Doyle and colleagues found that individuals who received mechanical ventilation and developed BPD may have lung function, as measured by the ratio of FEV₁ to forced vital capacity (FVC), that is declining at a faster rate compared with a control group who had received less mechanical ventilation and did not develop BPD (Doyle et al. 2006).

A number of neonatal variables have been associated with abnormal respiratory function later in life. Early gestational age at birth has been associated with worse airflow as measured by the FEV₁ (r = 0.788, p < 0.01) and the FEF_{25–75 %} (r = 0.745, p < 0.01) (Bader et al. 1987). Moreover, the total duration of ventilation was negatively associated with abnormal air flow as measured by the FEV₁ (r = −0.763, p < 0.01), FVC, FEF_{50 %} and FEF_{25–75 %} (Bader et al. 1987; Pelkonen et al. 1997). However, neither birth weight nor duration of oxygen supplementation correlated with resting lung function and none of these variables was associated with exercise performance as measured by peak oxygen consumption, even though exercise performance does not correlate with resting pulmonary function, as discussed later.

The prevalence of exercise-related morbidity such as cough, dyspnoea and wheeze is significantly higher in individuals who were mechanically ventilated as neonates and developed BPD (Doyle 2008; Gross et al. 1998; Bader et al. 1987; Kriemler et al. 2005; Vrijlandt et al. 2006). These cardiopulmonary limitations may not be evident at rest using standard respiratory function measurements but only become apparent when the respiratory and cardiac systems are put under stress during an exercise test (Doyle 2008; Gross et al. 1998; Bader et al. 1987; Kriemler et al. 2005; Vrijlandt et al. 2006; Narang et al. 2006). Many of the studies investigating these cardiopulmonary outcomes have used different methods of exercise testing, incorporating different protocols and work intensities, and have therefore displayed conflicting data (Doyle 2008; Gross et al. 1998; Bader et al. 1987; Kriemler et al. 2005; Vrijlandt et al. 2006; Narang et al. 2006; Baraldi et al. 1991; Jacob et al. 1997; Kilbride et al. 2003; Pianosi and Fisk 2000; Santuz et al. 1995). However, most studies describe ventilatory limitation of varying degrees. Some neonatal survivors with BPD demonstrate compensatory alterations in the ventilation strategy to achieve peak oxygen consumption close to predicted (Table 63.2) (Doyle 2008; Gross et al. 1998; Bader et al. 1987; Kriemler et al. 2005; Vrijlandt et al. 2006; Narang et al. 2006; Baraldi et al. 1991; Jacob et al. 1997; Kilbride et al. 2003; Pianosi and Fisk 2000; Santuz et al. 1995). The maximum rate of oxygen consumption during peak exercise in the mechanically ventilated BPD survivors is reduced on many occasions when compared with control groups, but does not often fall into clinically significant ranges (Table 63.2) (Doyle 2008; Bader et al. 1987; Kriemler et al. 2005; Vrijlandt et al. 2006; Narang et al. 2006; Baraldi et al. 1991; Jacob et al. 1997; Kilbride et al. 2003; Pianosi and Fisk 2000; Santuz et al. 1995). When investigating airway hyperreactivity or exercise-induced bronchoconstriction, many of the researchers have found a higher incidence in preterm survivors who received mechanical ventilation and oxygen supplementation for respiratory failure as neonates; see Table 63.2 (Doyle 2008; Gross et al. 1998; Bader et al. 1987; Kriemler et al. 2005; Vrijlandt et al. 2006; Narang et al. 2006; Baraldi et al. 1991; Jacob et al. 1997; Kilbride et al. 2003; Pianosi and Fisk 2000; Santuz et al. 1995). However, since the aetiology of mechanical ventilation-induced airway hyperreactivity and bronchoconstriction is poorly understood, it is difficult to gauge the degree to which genetic and immunological factors play a part (Doyle 2008; Gross et al. 1998; Bader et al. 1987; Kriemler et al. 2005; Vrijlandt et al. 2006; Narang et al. 2006; Baraldi et al. 1991; Jacob et al. 1997; Kilbride et al. 2003; Pianosi and Fisk 2000; Santuz et al. 1995).